Catecholamine Autotoxicitya Novel Target for Experimental Therapeutics: As highlighted in recent reviews (D. S. Goldstein, 2013; D.S. Goldstein, 2013), scientific integrative medicine links systems biology with integrative physiology and pathophysiology. Concepts of scientific integrative medicine include negative feedback regulation, compensatory activation of alternative effectors, primitive specificity of stress response patterns, and allostatic load, the latter explaining chronic degenerative diseases in terms of cumulative effects of wear and tear. According to the catecholaldehyde hypothesis, 3,4-dihydroxyphenylacetaldehyde (DOPAL), the immediate product of enzymatic oxidation of cytosolic dopamine by monoamine oxidase (MAO), challenges neuronal homeostasis throughout the lifespan of monoaminergic neurons and eventually contributes to induction of lethal positive feedback loops. The catecholaldehyde hypothesis predicts that MAO inhibition, especially when combined with an aldehyde scavenger, anti-oxidant, or divalent metal ion chelator, should attenuate or prevent autotoxic death of catecholamine neurons (Goldstein, Kopin, & Sharabi, 2014). A disease modification clinical trial could provide a key test of the hypothesis. A potential stumbling block, however, is that inhibition of MAO-A, the isoform responsible for DOPAL production in catecholaminergic neurons, renders patients vulnerable to the cheese effect. In the cheese effect, when patients on MAO inhibitors ingest tyramine-containing foodstuffs such as red wine and cheese, dangerous hypertensive paroxysms can ensue, due to decreased metabolic breakdown of tyramine by MAO-A in the gut. To avoid the cheese effect we are considering repurposing an MAO inhibitor patch that is approved as an anti-depressant. Alternatively, since MAO-B inhibitors decrease levels of MAO-A metabolites in humans (by mechanisms that remain obscure), an MAO-B inhibitor might interfere with intraneuronal formation of catecholaldehydes. We are also considering testing drugs that have the combined effects of inhibiting MAO, exerting anti-oxidant effects, and chelating divalent metal cations. In PD the loss of cardiac sympathetic neurons, once it begins, progresses extremely rapidly to completeness over a few years. Neuroimaging of myocardial noradrenergic innervation could therefore provide the main dependent measure in a proof of principle study. Although bench laboratory studies have consistently noted levodopa-induced cytotoxicity, clinical researchers have disagreed about whether levodopa/carbidopa therapy accelerates neurodegeneration in PD. Levodopa-related cytotoxicity occurs at least partly by enzymatic oxidation of cytoplasmic dopamine (DA) catalyzed by monoamine oxidase (MAO). Deuterated levodopa might offer a theoretically less toxic PD treatment, because of the deuterium isotope effect. Deuterium substitution at the alpha-carbon of levodopa stabilizes the carbon-nitrogen bond of the amine residue. As a result, deuterated DA derived from deuterated levodopa should be less susceptible to conversion to DOPAL by MAO. Our research collaborators have patented deuterated levodopa, and we plan to compare non-deuterated levodopa vs. deuterated levodopa in terms of the extent of generation of DOPAL. Precursor Therapy for Norepinephrine (NE) Deficiency: Many studies have supported the view that PD involves loss not only of central dopaminergic but also of central noradrenergic neurons. The NE pro-drug, L-dihydroxyphenylserine (L-DOPS, droxidopa, Northera) might be useful to treat neurobehavioral abnormalities resulting from central NE deficiency. Studies are under way to confirm an association between non-motor manifestations of Lewy body diseases and clinical laboratory indices of central NE deficiency. If these succeed, we may embark on experimental therapeutics trials of L-DOPS. A theoretical limitation is neurotoxicity due to increased formation of 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), the catecholaldehyde produced from oxidative deamination of NE. We have developed assay methodology for measuring DOPEGAL and are conducting bench laboratory studies comparing L-DOPS with other amino acids in terms of generation and effects of monoamine aldehydes. Targeting Neurocirculatory Abnormalities to Slow Cognitive Deterioration: Patients with PD often have orthostatic hypotension (OH) coupled with supine hypertension. This combination can be found even in early, untreated PD and is associated with white matter hyperintensities and cognitive dysfunction (Kim, et al., 2012; Kim, et al., 2014). Developing effective treatments for these neurocirculatory abnormalities would constitute a novel approach to retard or prevent dementia in PD. We showed previously that i.v. infusion of norepinephrine (NE), hand-titrated to maintain blood pressure during graded head-up tilting, temporarily eliminates OH (Goldstein, et al., 2012). Further development of a prosthetic baroreceptor would require testing of ambulatory inpatients undergoing NE infusion via a central i.v. catheter. We deferred this project in favor of collaborating with other members of the Autonomic Rare Diseases Clinical Research Consortium (RDCRC) who are developing an automated abdominal binder as a non-invasive means to treat OH. Whether the Autonomic RDCRC will continue is unclear at this time.